Short-Term Impact of Seizures and Mitigation Opportunities.

PURPOSE OF REVIEW: The burden of epilepsy is complex and consists of elements directly related to acute seizures as well as those associated with living with a chronic neurologic disorder. The purpose of this systematic review was to characterize short-term burdens of seizures and to explore the potential value of acute treatments to mitigate these burdens apart from reducing the risk of status epilepticus. RECENT FINDINGS: A systematic literature search was conducted using PubMed to identify articles published from January 1, 2017, to June 22, 2023, that described short-term burdens and acute treatments of seizures. Primary outcomes included those related to short-term burdens of seizures and the benefits of acute treatments to reduce short-term burdens. Of the 1332 articles identified through PubMed and 17 through other sources, 27 had relevant outcomes and were included in the qualitative synthesis. Seizure emergencies negatively affected short-term quality of life and the ability to conduct normal daily living activities and were associated with physical (injury) and financial (emergency transport, hospitalization) burdens. The use of acute treatment was associated with a rapid return (≤ 1 h) to normal function/self for both patients and caregivers and potentially lower healthcare utilization and costs. Seizure action plans may improve knowledge and comfort with seizure care, empowering patients and caregivers. The short-term burden of seizures can create a substantial negative impact on patients and caregivers. Acute treatments may reduce the short-term burdens of seizures in addition to their well-described role to reduce seizure activity and the risk for status epilepticus.

Treatment of prolonged seizure with diazepam nasal spray: An exploratory post hoc cohort analysis.

BACKGROUND: Benzodiazepines are used in first-line rescue therapy as immediate-use seizure medication for the treatment of seizure clusters and prolonged seizures. Their use varies across clinical practices and conditions, and they can be used promptly when indicated. Clinical studies have demonstrated seizure termination within 2 min when diazepam nasal spray is used to treat seizure clusters within 5 min, but the response when treating longer duration seizures in a cluster remains to be characterized. OBJECTIVE: To describe and assess timing and dosing of diazepam nasal spray in the subset of prolonged seizures within seizure clusters in a larger dataset of all treated seizure clusters collected during a long-term safety study of diazepam nasal spray. METHODS: Using timing data recorded in seizure diaries, this post hoc analysis and associated sensitivity analyses focused on prolonged seizures treated 5 to 15 min after the seizure start. Measures included time to treatment administration and time to seizure termination. Second-dose data were used as a proxy for effectiveness. RESULTS: In this group of seizure clusters treated 5 to 15 min after seizure start, median time drug administration was 6 min after seizure start, median time from drug administration to seizure termination was 7 min, and median overall seizure duration was 15 min. Sensitivity analyses by age, epilepsy type, and high seizure frequency confirmed this pattern. Use of a second dose occurred in 9.3 % of episodes, with the majority of second doses administered ≤ 4 h after the first dose. Safety results from the overall study showed 82.2 % of patients had ≥ 1 treatment-emergent adverse event (TEAE) irrespective of relationship to treatment, during a mean participation of âˆ¼ 1.5 years. In addition, 30.7 % patients had a serious TEAE, and 18.4 % had TEAEs deemed at least possibly related to the study drug, none of which were serious. No events of cardiorespiratory depression were reported. CONCLUSIONS: Although immediate use of diazepam nasal spray (within 5 min) resulted in quicker seizure termination, a treatment delay of 5 to 15 min still produced rapid termination of the seizure cluster with high first-dose effectiveness and an overall acceptable safety profile. These findings suggest that diazepam nasal spray maintains effectiveness in prolonged seizures within a cluster with delayed treatment.

Greater need for treatment optimization in patients with epilepsy initiating adjunctive therapy: Results of a retrospective claims analysis of antiseizure medication drug load in the United States.

BACKGROUND: This retrospective, observational study used US claims data to assess changes in antiseizure medication (ASM) drug load for a cohort of patients with epilepsy. METHODS: Adults (≥18 years) with a diagnosis of epilepsy (ICD-10 code G40.xxx) who started new adjunctive ASM treatment with one of 4 branded (brivaracetam, eslicarbazepine, lacosamide, perampanel) or 4 unbranded (carbamazepine, lamotrigine, levetiracetam, topiramate) ASMs between January 1, 2016 and December 31, 2020 were identified from IBM MarketScan® research databases (primary study population). Patients must have been continuously enrolled 360 days before the start of the new ASM (eligibility period). Follow-up was from the start of new ASM until Day 540 (∼18 months). The primary endpoint was concomitant ASM drug load, which included all ASMs except the new (comparator) ASM. A sensitivity analysis population included adults with epilepsy who were continuously enrolled for ≥ 180 days during at least one calendar year in the study period (2016-2020), whether or not the comparator ASM was new or existing during that period. Total ASM drug load, which included comparator ASM and concomitant ASMs, was assessed in the sensitivity analysis population. RESULTS: In total, 21,332 patients were included in the primary study population, of which 5767 initiated branded ASMs and 15,565 initiated unbranded ASMs. A total of 392,426 patients were included in the sensitivity analysis population during at least one calendar year 2016-2020. Concomitant ASM drug load increased in the 360 days prior to new ASM start and slightly declined thereafter. Mean concomitant ASM drug load for the primary population was 1.6 (SD 1.8) at new ASM start. Concomitant drug load was higher among those starting branded ASM comparators compared to those starting unbranded comparators. Mean total ASM drug load for patients increased over time and was approximately double for patients exposed to branded ASMs (mean range 2.1 to 2.7) compared to that of patients exposed to any unbranded ASM (mean range 1.0 to 1.3). CONCLUSION: Concomitant ASM drug load increased prior to addition of new ASM, with higher increases observed among patients starting branded vs unbranded ASMs, followed by slight decreases thereafter. Total drug load increased linearly among all patients. These findings underscore the need for ongoing ASM regimen evaluation and treatment optimization in patients with epilepsy.

Introduction to use of an acute seizure action plan for seizure clusters and guidance for implementation.

It is important for patients with epilepsy and their caregivers, including care partners, to understand the patient's seizure clusters and what to do when they occur. In many instances, seizure clusters are unique to each patient. The knowledge gained from understanding a patient's seizure cluster or seizure pattern provides a foundation for taking prompt action to prevent worsening to prolonged seizures, status epilepticus, and potentially death. Seizure action plans (SAPs), which are similar to the disease-related treatment action plans for other conditions, can be developed by a health care provider (HCP) in conjunction with the patient with epilepsy and/or caregivers, and SAPs are specifically customized for the individual patient and his or her seizure management. However, the current literature lacks unified guidance on how to design SAPs that will help prepare patients and caregivers for rapidly determining and initiating appropriate treatment of acute seizure emergencies in the community and at home. Here, we examine the current usage and value of SAPs for pediatric and adult patients with epilepsy, and we introduce the concept of the acute SAP (ASAP) for use specifically during seizure emergencies, such as seizure clusters. This type of standardized, simplified, and customized plan can rapidly and concisely provide patients and caregivers with a practical protocol to treat a seizure cluster consistently, appropriately, and in a timely manner. Details on potential content and formats of ASAPs are provided. Following this is a discussion of barriers to ASAP use that may affect HCPs or patients and caregivers, including lack of standardization, relevance, and personalization and pitfalls associated with technology. This leads into a discussion of guidance for developing, implementing, and updating ASAPs that suggests ways to address the barriers and ensure that the ASAP is best suited to the patient's needs.

Intracranial electroencephalographic biomarker predicts effective responsive neurostimulation for epilepsy prior to treatment.

OBJECTIVE: Despite the overall success of responsive neurostimulation (RNS) therapy for drug-resistant focal epilepsy, clinical outcomes in individuals vary significantly and are hard to predict. Biomarkers that indicate the clinical efficacy of RNS-ideally before device implantation-are critically needed, but challenges include the intrinsic heterogeneity of the RNS patient population and variability in clinical management across epilepsy centers. The aim of this study is to use a multicenter dataset to evaluate a candidate biomarker from intracranial electroencephalographic (iEEG) recordings that predicts clinical outcome with subsequent RNS therapy. METHODS: We assembled a federated dataset of iEEG recordings, collected prior to RNS implantation, from a retrospective cohort of 30 patients across three major epilepsy centers. Using ictal iEEG recordings, each center independently calculated network synchronizability, a candidate biomarker indicating the susceptibility of epileptic brain networks to RNS therapy. RESULTS: Ictal measures of synchronizability in the high-γ band (95-105 Hz) significantly distinguish between good and poor RNS responders after at least 3 years of therapy under the current RNS therapy guidelines (area under the curve = .83). Additionally, ictal high-γ synchronizability is inversely associated with the degree of therapeutic response. SIGNIFICANCE: This study provides a proof-of-concept roadmap for collaborative biomarker evaluation in federated data, where practical considerations impede full data sharing across centers. Our results suggest that network synchronizability can help predict therapeutic response to RNS therapy. With further validation, this biomarker could facilitate patient selection and help avert a costly, invasive intervention in patients who are unlikely to benefit.

Concurrent brain-responsive and vagus nerve stimulation for treatment of drug-resistant focal epilepsy.

OBJECTIVE: Clinical trials of a brain-responsive neurostimulator, RNS® System (RNS), excluded patients with a vagus nerve stimulator, VNS® System (VNS). The goal of this study was to evaluate seizure outcomes and safety of concurrent RNS and VNS stimulation in adults with drug-resistant focal-onset seizures. METHODS: A retrospective multicenter chart review was performed on all patients with an active VNS and RNS who were treated for a minimum of 6 months with both systems concurrently. Frequency of disabling seizures at baseline before RNS, at 1 year after RNS placement, and at last follow-up were used to calculate the change in seizure frequency after treatment. Data on adverse events and complications related to each device were collected. RESULTS: Sixty-four patients from 10 epilepsy centers met inclusion criteria. All but one patient received RNS after VNS. The median follow-up time after RNS implantation was 28 months. Analysis of the entire population of patients with active VNS and RNS systems revealed a median reduction in seizure frequency at 1 year post-RNS placement of 43% with a responder rate of 49%, and at last follow-up a 64% median reduction with a 67% responder rate. No negative interactions were reported from the concurrent use of VNS and RNS. Stimulation-related side-effects were reported more frequently in association with VNS (30%) than with RNS (2%). SIGNIFICANCE: Our findings suggest that concurrent treatment with VNS and RNS is safe and that the addition of RNS to VNS can further reduce seizure frequency.

Brooded coral offspring physiology depends on the combined effects of parental press and pulse thermal history.

Reef-building corals respond to the temporal integration of both pulse events (i.e., heat waves) and press thermal history (i.e., local environment) via physiological changes, with ecological consequences. We used a "press-pulse-press" experimental framework to expose the brooding coral Porites astreoides to various thermal histories to understand the physiological response of temporal dynamics within and across generations. We collected adult colonies from two reefs (outer Rim reef and inner Patch reef) in Bermuda with naturally contrasting thermal regimes as our initial "press" scenario, followed by a 21-day ex situ "pulse" thermal stress of 30.4°C during larval brooding, and a "press" year-long adult reciprocal transplant between the original sites. Higher endosymbiont density and holobiont protein was found in corals originating from the lower thermal variability site (Rim) compared to the higher thermal variability site (Patch). The thermal pulse event drove significant declines in photosynthesis, endosymbiont density, and chlorophyll a, with bleaching phenotype convergence for adults from both histories. Following the reciprocal transplant, photosynthesis was higher in previously heated corals, indicating recovery from the thermal pulse. The effect of origin (initial press) modulated the response to transplant site for endosymbiont density and chlorophyll a, suggesting contrasting acclimation strategies. Higher respiration and photosynthetic rates were found in corals originating from the Rim site, indicating greater energy available for reproduction, supported by larger larvae released from Rim corals post-transplantation. Notably, parental exposure to the pulse thermal event resulted in increased offspring plasticity when parents were transplanted to foreign sites, highlighting the legacy of the pulse event and the importance of the environment during recovery in contributing to cross-generational or developmental plasticity. Together, these findings provide novel insight into the role of historical disturbance events in driving differential outcomes within and across generations, which is of critical importance in forecasting reef futures.

Patient, caregiver, and healthcare professional perspectives on seizure control and treatment goals.

OBJECTIVE: To examine perspectives of adult patients with epilepsy, caregivers, and healthcare professionals (HCPs) on seizure freedom, seizure control, communication, and treatment goals. METHODS: Participants were recruited from online M3 panel and by Rare Patient Voice, and completed the self-administered online STEP Survey (Seize the Truth of Epilepsy Perceptions). Group comparisons used analysis of variance and chi-square tests. RESULTS: The STEP Survey was completed by 400 adult patients with epilepsy, 201 caregivers, and 258 HCPs (112 general neurologists, 96 epileptologists, 50 nurse practitioners/physician assistants). Significantly more patients (61%) and caregivers (66%) than HCPs (45%) agreed that seizure freedom is always a reasonable goal (P < 0.05). On average, patients considered 3.6 seizures/year to be "in control." Of their patients with focal seizures, HCPs reported 47% were seizure-free and 33% were "in control" (63% were having 1-12 seizures/year), and 20% were with "uncontrolled" seizures. Among patients, caregivers, and HCPs, ≥60% agreed that a defining characteristic indicating seizure control was having good quality of life. Patients, caregivers, and HCPs agreed that the emotional, psychological, and relational impact of seizures were least discussed (<50% of each group reporting discussion), but disagreed in their top priority for greater discussion (patients: sudden unexplained death in epilepsy [SUDEP]; HCPs: relational impact of seizures). Although ≥80% of patients and caregivers selected multiple patient life goals as very or extremely important, 49% of patients said they do not share life goals with their HCP. HCPs agreed that patients are not telling them everything they should about their epilepsy (73% of HCPs) or their life goals (81% of HCPs). CONCLUSIONS: Differing perspectives on seizure freedom, seizure control, communication priorities, and treatment goals that were identified in the STEP Survey provide opportunities to improve patient care and outcomes through more effective two-way communication and alignment of goals among patients with epilepsy, caregivers, and HCPs.

Recommendations for development of acute seizure action plans (ASAPs) from an expert panel.

PURPOSE OF REVIEW: Disease-related treatment action plans for acute exacerbations providing information that may be helpful for self-management for patients and caregivers are commonly used for chronic conditions such as asthma and diabetes. However, among patients with epilepsy, a review of the literature suggested that the majority did not have an action plan in place for acute seizure treatment. RECENT FINDINGS: Currently, there is a lack of unified guidance on seizure action plans (SAPs) in the literature. In the authors' opinion, available formats have limitations for practical use and may not be easily customizable to individual patients, and they are not often designed to provide simple-to-follow steps for rapid immediate steps to determine and initiate appropriate treatment of seizure emergencies. Our group reviewed current examples of SAPs and provided guidance on the development of acute seizure action plans (ASAPs) designed to facilitate rapid, appropriate acute care in the community and to be as useful as possible for a wide range of care partners, including those with limited experience. SUMMARY: This paper provides agreed upon expert opinion recommendations and considerations for goals, development process, types of content, and format for an ASAP.

Nutrient and sediment loading affect multiple facets of functionality in a tropical branching coral.

Coral reefs, one of the most diverse ecosystems in the world, face increasing pressures from global and local anthropogenic stressors. Therefore, a better understanding of the ecological ramifications of warming and land-based inputs (e.g. sedimentation and nutrient loading) on coral reef ecosystems is necessary. In this study, we measured how a natural nutrient and sedimentation gradient affected multiple facets of coral functionality, including endosymbiont and coral host response variables, holobiont metabolic responses and percent cover of Pocillopora acuta colonies in Mo'orea, French Polynesia. We used thermal performance curves to quantify the relationship between metabolic rates and temperature along the environmental gradient. We found that algal endosymbiont percent nitrogen content, endosymbiont densities and total chlorophyll a content increased with nutrient input, while endosymbiont nitrogen content per cell decreased, likely representing competition among the algal endosymbionts. Nutrient and sediment loading decreased coral metabolic responses to thermal stress in terms of their thermal performance and metabolic rate processes. The acute thermal optimum for dark respiration decreased, along with the maximal performance for gross photosynthetic and calcification rates. Gross photosynthetic and calcification rates normalized to a reference temperature (26.8°C) decreased along the gradient. Lastly, percent cover of P. acuta colonies decreased by nearly two orders of magnitude along the nutrient gradient. These findings illustrate that nutrient and sediment loading affect multiple levels of coral functionality. Understanding how local-scale anthropogenic stressors influence the responses of corals to temperature can inform coral reef management, particularly in relation to the mediation of land-based inputs into coastal coral reef ecosystems.